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J Biol Chem, Vol. 273, Issue 9, 5279-5287, February 27, 1998

Central Role of Ferrous/Ferric Iron in the Ultraviolet B Irradiation-mediated Signaling Pathway Leading to Increased Interstitial Collagenase (Matrix-degrading Metalloprotease (MMP)-1) and Stromelysin-1 (MMP-3) mRNA Levels in Cultured Human Dermal Fibroblasts

Peter Brenneisen, Jutta Wenk, L. Oliver Klotz^§, Meinhard Wlaschek, Karlis Briviba^§, Thomas Krieg, Helmut Sies^§, and Karin Scharffetter-Kochanek

From the  Department of Dermatology, University of Cologne, D-50924 Cologne, Germany and the ^§ Institute for Physiological Chemistry I, Heinrich-Heine-University Düsseldorf, D-40225 Düsseldorf, Germany

Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathological conditions. Ultraviolet B (UVB) irradiation has recently been shown to generate lipid peroxidation products and hydroxyl radicals (HO^·) with detrimental long term effects like cancer formation and premature aging of the skin. Here, we addressed the question of whether ferric/ferrous iron via the generation of ROS may mediate the UVB response, finally leading to connective tissue degradation, a hallmark in carcinogenesis and aging. Therefore, we studied the involvement of iron and ROS in the modulation of Jun N-terminal kinase 2 (JNK2) activity, c-jun and c-fos mRNA levels, key signaling steps in the transcriptional control of matrix-degrading metalloprotease (MMP)-1/interstitial collagenase and MMP-3/stromelysin-1 after UVB irradiation of human dermal fibroblasts in vitro. The iron-driven generation of lipid peroxides and hydroxyl radicals were identified as early events in the downstream signaling pathway of the UVB response leading to a 15-fold increase in JNK2 activity, a 3.5-fold increase in c-jun, to a 6-fold increase in MMP-1, and a 3.8-fold increase in MMP-3 mRNA levels, while virtually no alteration of c-fos mRNA levels were observed. Diminished generation of reactive oxygen species resulted in a significant reduction of JNK2 activity, c-jun, MMP-1, and MMP-3 mRNA levels after UVB irradiation compared with UVB-irradiated cells. Collectively, we have identified the iron-driven Fenton reaction and lipid peroxidation as possible central mechanisms underlying signal transduction of the UVB response.

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